HIV-infected persons appear to be at higher risk for chronic obstructive pulmonary disease (COPD), although the clinical manifestations and underlying mechanisms of HIV-associated COPD remain unclear. The ongoing Study of HIV Infection in the Etiology of Lung Disease (SHIELD) cohort has recruited >2,000 participants to prospectively evaluate how HIV infection may enhance susceptibility to COPD. SHIELD data suggest that poorly controlled plasma HIV viremia accelerates lung function decline. Further, HIV-associated COPD is characterized by CD4+ T cell depletion occurring to a greater extent in the lung mucosa than in the periphery. Based on these findings, our central hypothesis is that the development and clinical manifestations of HIV- associated COPD are driven, at least in part, by HIV viral replication, CD4+ T cell depletion and CD8+ T cell immune activation in the lung mucosa. In Aim 1, we identify and differentiate clinical, physiologic, and radiographic COPD phenotypes in HIV-infected compared to uninfected persons. Then, we prospectively follow these participants to define the clinical and patient-reported consequences of COPD phenotypes. In Aim 2, we determine whether the presence and severity of HIV-associated COPD is correlated with depletion of lung CD4+ T cells. In Aim 3, we test the hypothesis that lung CD4+ depletion and dysregulation is due to HIV infection and replication. In Aim 4, we examine whether there is increased lung CD8+ T cell immune activation in HIV-associated COPD, due at least in part, to loss of CD4+ T cell regulatory mechanisms. Our multidisciplinary team of investigators provides clinical and research expertise in HIV, pulmonary diseases, and immunology, and have an established track record of productive collaboration in HIV and COPD. SHIELD provides an ideal study population and research infrastructure to perform these clinical and mechanistic studies. In summary, this proposal directly addresses critical gaps in our understanding of the clinical spectrum and consequences of HIV-associated COPD and will identify key biologic mechanisms contributing to the disease. Findings will inform the clinical management and development of interventions targeting HIV- associated COPD, and may also inform broader strategies for COPD in non-HIV infected populations.